RNA-sequencing of serial biopsies from 3 patients treated with Capivasertib (AZD5363)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE144794 | GEO | 2020/06/30
REPOSITORIES: GEO
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Project description:RNA-sequencing of serial biopsies from 3 patients treated with Capivasertib (AZD5363)
| PRJNA609909 | ENA
Project description:Paclitaxel -resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of Aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. These findings are fully recapitulated in a patient derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.
2024-06-21 | GSE264630 | GEO
Project description:Triple negative breast cancer (TNBC) represents a therapeutic challenge where standard chemotherapy is limited to paclitaxel. MBQ-167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ-167 in combination with paclitaxel in TNBC pre-clinical models, as a prelude to safety trials of this combination in advanced breast cancer patients. Individual MBQ-167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared to paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB-231 and MDA-MB-468), individual MBQ-167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, while MBQ-167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ-167 and paclitaxel decreased established lung metastases by ~80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ-167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ-167 and Paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ-167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ-167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action.
2024-08-05 | GSE272653 | GEO
Project description:Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC). Despite the good initial responses, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), activation of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve and paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced the potency of BV6, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance
2017-01-26 | GSE86839 | GEO
Project description:Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. For each sample, 500 ng of total RNA were used to synthesize biotinylated cRNA with Illumina RNA Amplification Kit (Ambion, Austin, TX). Synthesis was carried out according to the manufacturersâ instructions. From each sample, technical triplicates were produced and 750 ng cRNA were hybridized for 18h to Human HT-12_V3_0_R1 Expression BeadChips (Illumina, San Diego, CA). Hybridized chips were washed and stained with streptavidin-conjugated Cy3 (GE Healthcare, Milan, Italy). BeadChips were dried and scanned with an Illumina Bead Array Reader (Illumina).
2016-12-01 | E-MTAB-5286 | biostudies-arrayexpress
Project description:Background: PIK3CA mutations are observed in >30% of breast cancers, which are more common in estrogen receptor (ERα)-positive breast cancer compared with ERα-negative breast cancer. AKT1, 2, and 3 isoforms, major isoforms downstream of PI3K, modulate ERα activity. It is unknown whether PIK3CA mutation leads to preferential activation of specific AKT isoforms with an ability to modulate ERα function. Methods: Gene expression arrays were performed on parental, AKT1 knockdown or AKT2 knockdown MCF-7 breast cancer cells with or without estradiol treatment for three hours. Results: AKT1 had a dominant role in ERα:estradiol-dependent gene expression and proliferation. We have identified a unique gene expression signature that is dependent on ERα, estradiol, AKT1 and the pioneer factor FOXA1. Overexpression of this signature was associated with better outcome in patients with ERα-positive breast cancer. In contrast, AKT2 controlled global gene expression.
2016-08-10 | GSE60759 | GEO
Project description:Purpose:Assess the reprogramming of H3K4me1, H3K4me3, H3K27ac and H3K27me3 in paclitaxel-resistant triple-negative breast cancer cells relative to paclitaxel-sensitive cells Methods: ChIP-seq was performed on paclitaxel-treated MDA-MB-436 cells that are resistant to Paclitaxel (R20A, R20B, R20C) and in control-treated (DMSO) parental MDA-MB-436 cells that are sensitive to Paclitaxel (DMSO) Results: Using we mapped about 20 million sequence reads per sample to the human genome (hg19) and identified significant peaks in each cell lines using MACS.2.0 tool. Conclusions: Our study identified major reprogramming of H3K27me3 in the taxol-resistant TNBC cells relative to parental (TNBC cells), with loss of discrete H3K27me3 peaks in the resistant cells concomittent to acquisition of clusters of H3K27me3.
2020-08-18 | GSE113684 | GEO
Project description:Purpose:Assess the difference in gene expression of taxol-resistant TNBC cells relative to parental cells (MDA-MB-436 and HS 578t) Methods: RNA-seq was performed on paclitaxel-treated MDA-MB-436 cells that are resistant to Paclitaxel (R20A, R20B, R20C) and in control-treated (DMSO) parental MDA-MB-436 cells that are sensitive to Paclitaxel (DMSO) Results: We mapped about 20 million sequence reads per sample to the human genome (hg19) and identified identified differentially expressed genes Conclusions: Our study identified genes significantly enriched or repressed in taxol-resistant cells relative to parental cells in both TNBC models (MDA_MB-436 and HS 578T)
2020-08-18 | GSE113685 | GEO
Project description:Despite the progress in immunotherapies, leading immune checkpoint inhibitors are only effective in a subset of patients. The efficacy of atezolizumab, an anti-PD-L1 antibody, in triple negative breast cancer (TNBC) is limited for unknown reasons. We utilized single-cell RNA- and ATAC-sequencing to examine the dynamics of immune cells in metastatic TNBC patients treated with paclitaxel or its combination with atezolizumab. We found that paclitaxel selectively damaged tumor-reactive T cells while atezolizumab was effective in a small set of patients with high levels of baseline B cells and CXCL13+ T cells. B cells concertedly expanded with CXCL13+ T cells in responsive patients following paclitaxel plus atezolizumab treatment. Our data highlight the importance of potential tumor-reactive T cells and their orchestrators in the effective response to anti-PD-L1 therapies, and reveal drawbacks of existing clinical trials for TNBC.
2021-09-15 | GSE169246 | GEO
Project description:Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy, however responses are typically short-lived1,2. Thus, there is an urgent need to develop more effective treatments. PI3K pathway components represent plausible therapeutic targets, as approximately 70% of TNBCs have PIK3CA/AKT1/PTEN alterations3–6. However, unlike hormone receptor-positive tumors, it is still unclear if or how PI3K pathway inhibitors will be effective in triple-negative disease7. Here we identify a promising AKT inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors potently synergize with agents that suppress the histone methyltransferase, EZH2, and promote robust tumor regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once differentiated, these agents kill TNBCs by hijacking signals that normally drive mammary gland involution. Finally, using machine learning approach, we developed a classifier that can be used for patient selection. Together these findings identify a promising therapeutic strategy for this highly aggressive tumor type and illustrate how deregulated epigenetic enzymes can insulate tumors from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.
2024-07-08 | GSE252382 | GEO